Abstract 3494: Durable and potent in vitro T cell activity with repeated exposure to CDR404, a potential best-in-class T cell engager targeting MAGE-A4

作者：Alessio Vantellini, Nora Wettstein, Melissa Vrohlings, Stephanie Jungmichel, André Luis Fonseca da Silva, Alice Langer, Anna Howald, Zoi Barou, Daniel Lenherr-Frey, Matteo Morotti, Christian Leisner, Swethajit Biswas, Leonardo Borras · 发表于：Cancer Research · 年份：2025 · DOI：10.1158/1538-7445.am2025-3494 · 研究领域：Immunotherapy and Immune Responses、CAR-T cell therapy research

Abstract T cell engagers (TCEs) targeting the melanoma antigen gene A4 (MAGE-A4) have entered first-in-human trials for HLA-A*02:01+ patients with MAGE-A4 expressing solid tumors. CDR404 is a bispecific antibody-based TCE that binds bivalently to the MAGE-A4230-239 peptide on HLA-A*02:01 and monovalently to CD3. The safety, tolerability and preliminary therapeutic efficacy of CDR404 are currently being evaluated in a dose-finding Phase 1 trial in multiple solid cancers including NSCLC (NCT06402201). The only other MAGE-A4 targeting TCE currently in clinical trial is a TCR-based TCE with a low affinity T cell recruiter, bearing an Fc region (TCR-TCE-Fc). Therefore, there are fundamental differences in format, functionality and pharmacology between these two TCE molecules. This preclinical study provides novel mechanistic insights into the persistence of cancer cell killing with repeated dosing of CDR404, comparing it to the TCR-TCE-Fc molecule. Since upregulation of PD-1 is an obligate immunosuppressive brake to T cell activation, we additionally investigated the in vitro killing activity of a CDR404 and Pembrolizumab combination compared to CDR404 alone. In co-culture assays of MAGE-A4+/HLA-A*02:01+ NSCLC cells (NCI-H1755) and human PBMCs, CDR404 induced higher levels of T cell activation, reflected by activation (CD69, CD25) and proliferation (Ki67) markers, and more potent tumor cell killing compared to the TCR-TCE-Fc. Higher potency of CDR404 was confirmed on different MAG...